1. Field
The invention relates to a new process for the preparation of retiferol derivatives of the formula: 
wherein
A is xe2x80x94Cxe2x95x90Cxe2x80x94 or xe2x80x94CHxe2x95x90CHxe2x80x94, and
R1 and R2 are independently of each other lower alkyl or lower perfluoroalkyl.
2. Description
Compounds of formula I can be utilized to treat or prevent hyperproliferative skin diseases such as psoriasis, basal cell carcinomas, disorders of keratinization and keratosis neoplastic diseases and disorders of the sebaceous glands such as acne and seborrhoic dermatitis. The compounds of formula I can also be utilized in reversing the conditions associated with photodamage, particularly for the oral or topical treatment of the skin damaged through sun exposure, the effects of wrinkling, elastosis and premature aging, especially for the treatment of psoriasis. Such compounds are known and disclosed in WO 99/43646.
The subject invention provides a process for preparing a compound of the formula: 
wherein A is xe2x80x94Cxe2x89xa1Cxe2x80x94 or xe2x80x94CHxe2x95x90CHxe2x80x94 and R1 and R2 each independently are lower alkyl or lower perfluoroalkyl. This process comprises coupling a compound of the formula: 
wherein X1 and X2 are hydroxy protecting groups, with a compound of the formula: 
wherein A, R1, R2 are as above and Y is a hydroxy protecting group, to produce the compound of formula I. Preferred hydroxy protecting groups, X1 and X2, are Si(C1-C4-alkyl)Me2 or a group R3COxe2x80x94 where R3 is lower alkyl or mono-chlorinated lower alkyl and Y is Si(C1-C4-alkyl)3. It is also preferred where A is xe2x80x94CHxe2x95x90CHxe2x80x94.
The subject invention also provides a process for preparing a compound of the formula: 
wherein A is xe2x80x94Cxe2x89xa1Cxe2x80x94 or xe2x80x94CHxe2x95x90CHxe2x80x94 and R1 and R2 each independently are lower alkyl or lower perfluoroalkyl. The process comprises coupling a compound of formula: 
wherein X1 and X2 are hydroxy protecting groups, with a compound of formula: 
wherein A, R1, R2 are as above and Y is a hydroxy protecting group to produce the compound of formula I. Favorably, X1 and X2 are each independently Si(C1-C4-alkyl)Me2 or a group R3COxe2x80x94 where R3 is lower alkyl or mono-chlorinated lower alkyl and Y is Si(C1-C4-alkyl)3. It is also preferred that A is xe2x80x94CHxe2x95x90CHxe2x80x94.
Another process provided by the subject invention is for preparing a compound of the formula: 
wherein R1 and R2 are each independently lower alkyl or lower perfluoroalkyl. This process comprises coupling a compound of formula: 
wherein R3 is lower alkyl or mono-chlorinated lower alkyl with a compound of formula: 
wherein R1, R2 are as above and Y is a Si(C1-4-alkyl)3. The protected hydroxy groups are then deprotected to obtain a compound of formula Ia.
Yet another inventive process is for preparing a compound of the formula: 
wherein R3 is lower alkyl or mono-chlorinated lower alkyl. This process involves protecting the hydroxy groups of the trans/cis/trans compound of the formula: 
or protecting the hydroxy groups of the all cis 1,3,5-trihydroxycyclohexane, to obtain the compound of the formula: 
wherein R3 is lower alkyl or mono-chlorinated lower alkyl). In the case of the all cis 1,3,5-trihydroxycyclohexane, this involves obtaining the protected all cis 1,3,5-trihydroxycyclohexane wherein the hydrogen atoms of the hydroxy groups have been replaced by R3 as above. The R3CO-group is then hydrolyzed in the 5-position in a biphasic water/organic solvent system in an enzymatic reaction to obtain a product of the formula: 
wherein R3 is as above. The hydroxy group o this compound is then oxidized to obtain a compound of formula IIa. The process beneficially uses enzymatic reaction lipases of the EC-class 3.1.1.3 or 3.1.1.34.
A further inventive process prepares a compound of the formula: 
wherein X1 is Si(C1-4-alkyl)Me2 or R3COxe2x80x94 where R3 is lower alkyl or mono-chlorinated lower alkyl. This process comprises protecting one hydroxy group of a compound of the formula: 
to obtain a compound of the formula: 
wherein X1 is as above. This compound is then acylated via an enzyme at a further hydroxy group of a compound of the formula (3) in a non-aqueous acylation solvent to obtain a compound of the formula: 
wherein X1 is as above and R3xe2x80x2 is methyl. The configuration of the carbon atom which carries the remaining unprotected hydroxy group in compound of formula (4) is then inverted and the R3xe2x80x2 OCxe2x80x94 group is cleaved to form a hydroxy derivative. The hydroxy group is then oxidized to obtain a compound of formula IIb. A preferred enzyme is a lipase of the EC-class 3.1.1.3 or lipoprotein lipases of the EC-class 3.1.1.34.
Another inventive process is for preparing a compound of the formula: 
wherein R1, R2 are each independently lower alkyl or lower perfluoroalkyl and Y is Si(C1-4-alkyl)3. This process comprises reacting a compound of the formula: 
wherein R1, R2 and Y are as above, with Me3SiCH2CO2R5, Ph3Pxe2x95x90CHxe2x80x94CO2R5 or (EtO)2P(O)CH2CO2R5, wherein R5 is lower alkyl; to obtain the compound of the formula: 
wherein R1, R2, R5 and Y are as above. The ester group is then reduced to obtain the hydroxy derivative of the compound of formula (10). This is coupled with 5-mercapto-1-phenyl-tetrazole or 2-mercapto-benzothiazole to obtain the compound of the formula: 
wherein R1, R2 and Y are as above, The sulfanyl group of the compound of the formula 11 to then oxidized to obtain the compound of formula IIIa.
The subject invention provides a compound of the formula: 
wherein R1 and R2 are each independently lower alkyl or lower perfluoroalkyl, Y is Si(C1-4-alkyl)3 and R5 is a lower alkyl.
In addition, the invention provides a compound of the formula: 
wherein R1 and R2 are each independently lower alkyl or lower perfluoroalkyl and Y is a Si(C1-4-alkyl)3.
Also provided is a compound of the formula: 
wherein R1 and R2 are each independently lower alkyl or lower perfluoroalkyl and Y is Si(C1-4-alkyl)3.
Another inventive process is for preparing a compound of the formula: 
wherein R1 and R2 are each independently lower alkyl or lower perfluoroalkyl. This process comprises coupling a compound of the formula: 
wherein R4 is a Si(C1-4-alkyl)Me2 with compound of the formula: 
wherein R1 and R2 are each independently lower alkyl or lower perfluoroalkyl. The protected hydroxy group is then deprotected to obtain a compound of the formula Ia.
It is preferred when the subject process forms the compound (1R,3R)-5-[(2E,9Z)-12,12,12-trifluoro-11-hydroxy-7,7-dimethyl-11-trifluoromethyl-dodeca-2,9-dienylidene)-cyclohexane,-1,3-diol.
The subject invention will now be described in terms of its preferred embodiments. These embodiments are set forth to aid and understand the invention but are not to be construed as limiting.
In general the invention relates to a new process for preparing retiferol derivatives of the formula 
wherein
A is xe2x80x94Cxe2x89xa1Cxe2x80x94 or xe2x80x94CHxe2x95x90CHxe2x80x94, and
R1 and R2 are independently of each other lower alkyl or lower perfluoroalkyl.
The term xe2x80x9clower alkylxe2x80x9d as used herein denotes straight chain or branched alkyl residues containing 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl.
The term xe2x80x9clower perfluoroalkylxe2x80x9d denotes lower alkyl groups as defined above wherein the hydrogen atoms are substituted by fluorine, such as in trifluoromethyl, pentafluoroethyl, perfluoropropy, and the like.
In the structural formulas presented herein, a broken bond () denotes that the substituent is below the plane of the paper and a wedged bond () denotes that the substituent is above the plane of the paper.
Although compounds of formula I can be prepared as described in WO 99/43646, these compounds can be prepared more efficiently in a lower number of reaction steps and in a higher yield by the inventive processes depicted in scheme A, namely by
method A which comprises the coupling of ketones of formula II with compounds of formula III or by
method B which comprises the coupling of phosphinoxides of formula IV with aldehydes of formula V, 
wherein A, R1 and R2 are as defined above and
X1, X2 and Y are hydroxy protecting groups.
The xe2x80x9chydroxy protecting groupsxe2x80x9d as used herein are for X1 and X2 independently of each other a mono alkyl dimethyl-silyl group [Si(C1-4-alkyl)Me2], preferably a tert-butyldimethyl-silyl group (TBS) or an acyl group (R3COxe2x80x94), wherein R3 signifies lower alkyl or mono chlorinated lower alkyl; and for Y a trialkyl-silyl group [Si(C1-4-alkyl)3], preferably a triethyl-silyl group (SiEt3) or a trimethyl-silyl group (SiMe3).
The term xe2x80x9cmono chlorinated lower alkylxe2x80x9d as used herein denotes straight chain or branched alkyl residues containing 1 to 4 carbon atoms with one chloro atom, such as chloromethyl, chloroethyl, chloropropyl, chloroisopropyl, chlorobutyl, chloro isobutyl or chloro tert-butyl.
The invention is thus concerned with new processes for the preparation of compounds of formula I, according to scheme A, by
method A, which comprises the coupling of ketones of formula II with compounds of formula III or by
method B, which comprises the coupling of phosphinoxides of formula IV with aldehydes of formula V.
The preferred method for the preparation of retiferol derivatives of formula I, wherein A is a double bond (compounds of formula Ia) according to scheme 1, is by coupling of the ketones of formula II, wherein X1 and X2 are R3COxe2x80x94 groups (compounds of formula IIa), with compounds of formula III, wherein A is a double bond (compounds of formula IIIa) according to method A in a two-step reaction, 
where the symbols are as defined above.
In step 1.1, the bis-acylated ketone of formula IIa is coupled with a compound of formula IIIa in the presence of a strong base, obtaining a fully hydroxy group protected derivative of the compound of formula Ia.
As a strong base n-butyl lithium (n-BuLi) or lithium diisopropylamide (LDA) can be used, a preferred strong base is LiN(SiMe3)2.
The reaction is carried out in solvents such as hydrocarbons preferably toluene, or ethers, an especially preferred solvent is tetrahydrofuran (THF); at a reaction temperature from xe2x88x92100xc2x0 to +60xc2x0, an especially preferred temperature range is xe2x88x9280xc2x0 to 20xc2x0.
In step 1.2, the fully hydroxy group protected derivative of the compound of formula Ia is reacted in the presence of a base to cleave the protecting groups to form the retiferol compound of formula Ia.
Bases for the deprotection reaction in step 1.2 are KOH, NaOH, Na2CO3 or NH4OH, preferably K2CO3.
The reaction is carried out in solvents such as C1-C6 alcohols, or water, or mixtures of the mentioned C1-C6 alcohols with water, a preferred solvent is MeOH; at a reaction temperature from xe2x88x9210 to +50xc2x0, especially preferred at 20xc2x0.
The term xe2x80x9cC1-C6 alcoholsxe2x80x9d as used herein denotes straight chain or branched alkyl residues containing 1 to 6 carbon atoms with one hydroxy group, such as methanol, ethanol, propanol, isopropanol, butanol, isobutanol, tert-butanol, pentanol or hexanol.
Preferred are processes for the preparation of compounds of formula I wherein A is a double bond xe2x80x94Cxe2x95x90Cxe2x80x94, more preferred of compounds of formula I wherein A represents a cis configurated double bond, for example (1R,3R)-5-[(2E,9Z)-12,12,12-trifluoro-11-hydroxy-7,7-dimethyl-11-trifluoromethyl-dodeca-2,9-dienylidene)-cyclohexane-1,3-diol.
In the following, the inventive processes for the preparation of the intermediates of formula II and III for the preparation of retiferol derivatives of formula I are described. The compounds of formula II may be prepared according to EP 0 516 410. However, it has been found that these compounds are prepared more effectively in a lower number of reaction steps and in a higher yield by the processes depicted in schemes 2 and 3, namely by new processes for the stereospecific synthesis of compounds of formula IIa and IIb.
The reaction depicted in scheme 2 is starting with commercially available trans/cis/trans 1,3,5-trihydroxycyclohexane of formula (a) optionally containing all cis 1,3,5-trihydroxycyclohexane, 
wherein R3 is lower alkyl or mono chlorinated lower alkyl except the tert-butyl group.
In step 2.1, the hydroxy groups of trans/cis/trans 1,3,5-trihydroxycyclohexane of formula (a) and all cis 1,3,5-trihydroxycyclohexane are protected with R3COxe2x80x94 groups, according to standard conditions, to obtain the acylated triol of formula (1) and acylated all cis 1,3,5-trihydroxycyclohexane.
In step 2.2, the protecting R3COxe2x80x94 group in the 5-position of the trans isomer of the trans/cis/trans mixture of the acylated triol (1) is regio- and stereoselectively hydrolyzed by an enzymatic reaction to a mono hydroxy-bis acylated compound of formula (2), whereas the all cis isomer which may be present remains unreacted in the mixture and is removed. The reaction is carried out in water at a pH in the range of 6.5-8.0, preferably in the presence of an organic co-solvent.
The reaction is preferably carried out with a mixture of acylated trans/cis/trans 1,3,5-trihydroxycyclohexane of formula (1) and all cis 1,3,5-trihydroxycyclohexane.
For the above enzymatic reaction lipases of the EC-class 3.1.1.3 or 3.1.1.34 are used, preferably lipases from yeast of Genus Candida, especially preferred of Candida rugosa (former classification C. cylindracea).
Such lipases are commercially available as for example lipase MY and OF from Meito Sangyo, lipase AY from Amano, Chirazyme L-3 from Roche Diagnostics, Lipase F5 from Enzymatix (now: Chiroscience) or C. rugosa-lipases from Sigma or Fluka.
Preferred are the lipases MY, AY or Chirazyme L-3, especially preferred is the lipase OF.
The reaction is carried out in water, preferably in the presence of an organic co-solvent to obtain a biphasic water/organic solvent-system, which increases the selectivity and the activity of the lipases in the enzymatic reaction. Co-solvents for the reaction are non- or medium-polar solvents, such as alkanes or cycloalkanes, an especially preferred co-solvent is cyclohexane.
The reaction is further characterized in that the aqueous system contains the biochemically usual salts, such as NaCl or KCl in a concentration of 0.1-0.5 M, preferred 0.1 M, at a pH in the range of 6.5-8.0, buffered by 2-20 mM solutions of sodium or potassium phosphate.
Instead of the above salts, ingredients such as LiSCN, Na2SO4 or polyhydric alcohols or carbohydrates such as D-glucose can be used at the same concentration.
In a further aspect of step 2.2, the lipases can be used in an immobilized form.
The substrate concentration in this reaction is in the range of 1-20%, preferably in the range of 1-10%.
The reaction temperature for the above reaction is between the freezing point of the system and ambient temperature, preferably the temperature is dose to the freezing point of the system.
In step 2.3, the unprotected hydroxy group of mono hydroxy-bis acylated compounds of formula (2) is oxidized in the presence of an oxidant to form bis acylated ketones of formula IIa.
The oxidation is carried out in the presence of oxalyl chloride and dimethyl sulfoxide (DMSO) (Swern method), 1,3-Dicyclohexylcarbodiimide (DCC) and DMSO (Pfitzner-Moffatt method), pyridine-SO3-complex and DMSO or (CH3)2S with N-chlorosuccinimide (Corey-Kim method), a preferred oxidation method is the oxidation with NaOCl in the presence of 2,2,6,6-tetramethylpiperidin-1-oxyl radical (TEMPO) as a catalyst.
The reaction is carried out in solvents such as ethers e.g. tert-butyl methyl ether (TBME), esters e.g. ethyl acetate, hydrocarbons e.g. toluene, or halogenated hydrocarbons especially preferred dichloromethane, at a reaction temperature from xe2x88x92100xc2x0 to +50xc2x0, an especially preferred temperature for the NaOCl/TEMPO oxidation is 0xc2x0.
A further embodiment of the invention is the process for the preparation of compounds of formula II, wherein X1 is as defined above except the MeCO-group and X2 is a tert-butyl-COxe2x80x94 group (compounds of formula IIb). The reaction is carried out according to scheme 3, starting with commercially available all-cis 1,3,5-trihydroxycyclohexane of formula (b), 
wherein the symbols are as defined above and R3xe2x80x2 is a methyl group.
In step 3.1, one hydroxy group of cis-cyclohexane-1,3,5-triol of formula (b) is protected in the presence of a base, according to standard conditions, to obtain the corresponding mono protected triol of formula (3).
This reaction is preferably carried out with tert-butyldimethylsilyl triflate (TBSOTf) as protecting reagent, an especially preferred protecting reagent is tert-butyldimethylsilyl chloride (TBSCl). Both protecting reagents are yielding to mono protected compound of formula (3), wherein X1 is a tert-butyldimethyl-silyl group (TBS).
In a preferred way, the above reaction is carried out with a mixture of bases such as NaH and NEt3, in a molar ratio of 1.0:1.1, in solvents such as ethers, preferably THF and at a reaction temperature of xe2x88x9220xc2x0 to +60xc2x0, especially preferred at a temperature of 20xc2x0 to 50xc2x0.
In step 3.2, a further hydroxy group of compounds of formula (3) is protected by an enzymatic acylation reaction, in the presence of an enzyme, in a non-aqueous system using the acyl donor as a solvent and optionally with a co-solvent. The reaction leads regio- and stereoselectively to a mono bis protected compound of formula (4).
The reaction is further characterized in that the formation of a di-acylated derivative is suppressed, that compound of formula (4) is obtained in enantiomeric excess (ee) higher than 99% ee, that the enzyme can be recycled, and that the substrate concentration is in the range of 1-20%.
Preferred enzymes for the above enzymatic reaction are lipases of the EC-class 3.1.1.3 or lipoprotein lipases of the EC-class 3.1.1.34, preferred are microbial lipases from Geni such as Candida, Pseudomonas, Alcaligenes, Aspergillus, Rhizopus, Penicillium, HumicoIa (newly classified as Thermomyces), Chromobacterium, Burkholderia or Mucor. Lipase from pig pancreas is also suitable.
Commercial available examples for lipases, which can be used in this reaction are: Candida rugosa (former classified as C. cylindracea) from Meito Sangyo (lipase MY or OF), from Amano (lipase AY), from Roche Diagnostics (Chirazyme L-3), from Enzymatix (now: Chiroscience; lipase F5), from Sigma or Fluka, Candida antarctica from Novo (Lipase SP-525 and SP-526) or from Roche Diagnostics (Chirazyme L-2 and L-5), from Candida utilis (Fluka), Pseudomonas (for example P. cepacia, P. fluoreszens and others) from Amano (lipase PS or AK), from Toyobo (lipase LPL-311), from Roche Diagnostics (Chirazyme L-6), from Fluka (lipase SAM) or from Enzymatix (lipase B1), Alcaligenes sp. from Meito Sangyo (lipase PL or QL), Aspergillus niger from Amano (lipase AP), Rhizopus delemar from Amano (lipase D), from Penicillium camemberti (former P. cyclopium) from Amano (lipase G), Humicola lanuginosa from Amano (lipase CE) or Enzymatix (now: Chiroscience; lipase F13), Chromobacterium viscosum from Sigma or Toyo Jozo, Burkholderia sp. from Roche Diagnostics (Chirazyme L-1), Mucor javanicus from Amano (lipase M-AP) or Mucor mieheifrom Novo (Lipozyme IM-20) or from Roche Diagnostics (Chirazyme L-9).
A preferred lipase is Chirazyme L-6, an especially preferred lipase is QL.
In a further aspect of step 3.2 the lipases can be optionally used in an immobilized form.
In the above enzymatic reaction, the usual acyl donors such as esters or anhydrides can be used. The preferred acyl donors are those to carry out the acylation step irreversibly such as enol esters,. e.g. vinyl ester or isopropenyl esters. Preferred solvents for the reaction are vinyl esters or ethyl acetate, an especially preferred solvent is vinyl acetate, or anhydrides preferably acetic anhydride.
The reaction is optionally carried out with co-solvents which are non polar up to medium polar like alkanes or cycloalkanes. Preferred co-solvents are ketones such as methyl isobutyl ketone, or aromatic solvents, ethers, preferably TBME or diisopropyl ether.
Preferably, the reaction is carried out in vinyl acetate or in a mixture of vinyl acetate in ethyl acetate with a concentration of vinyl acetate higher than 1 eq relatively to the substrate and at a reaction temperature from 0xc2x0 to +40xc2x0, especially preferred at ambient temperature.
The term xe2x80x9cenantiomeric excessxe2x80x9d (ee) as used herein signifies the purity of a mixture of enantiomers and it is calculated according to known methods.
In step 3.3, the configuration of the carbon atom which carries the remaining unprotected hydroxy group in compound of formula (4) is inverted by reaction with tert-butyl-COOH, according to the Mitsunobu method, to obtain the fully protected triol of formula (5).
The reaction is carried out in the presence of C1-4-alkyl azodicarboxylates and P(aryl)3, especially preferred is iso-propyl azodicarboxylate (for safety reasons) in the presence of triphenyl phosphane (PPh3).
The term xe2x80x9carylxe2x80x9d as used herein signifies in the scope of the present invention a phenyl group or phenyl groups which are monosubstituted in the ortho-, meta- or para- position. Suitable substituents for the phenyl group are C1-4-alkyl groups, preferably a methyl group, for example tolyl or xylyl.
The above reaction can be carried out in solvents such as ethers, e.g. THF; esters e.g. ethyl acetate; hydrocarbons e.g. toluene or halogenated hydrocarbons preferably dichloromethane; and at a reaction temperature from xe2x88x9260xc2x0 to +60xc2x0, especially preferred at a temperature of 0xc2x0.
In step 3.4, the R3xe2x80x2 OCxe2x80x94 group of the fully protected triol of formula (5) is cleaved off to form the hydroxy derivative of the compound of formula (5).
The above reaction is carried out in the presence of a base. The bases, solvents and reaction temperature suitable for this reaction are as described in step 1.2.
In step 3.5, the oxidation of the deprotected hydroxy group of the derivative of the compound of formula (5) is carried out as described in step 2.3, obtaining the bis hydroxy protected ketone of formula IIb.
Another preferred aspect of the invention is the synthesis of intermediates of formula III, wherein A is a double bond (compound of formula IIIa) starting with compounds of formula (9), which are synthesized according to scheme 4, 
wherein the symbols are as defined above.
In step 4.1, 4-chlorobutyl-t.-butyl ether (6), which is prepared according to the method described in A. Alexakis, M. Gardette, S. Colin, Tetrahedron Letters, 29, 2951, 1988, is condensed with commercially available mesityl oxide in the presence of Mg and a catalyst, to obtain the compound of formula (7).
Catalysts in this reaction are CuCl or CuBr, a preferred catalyst is CuI in an amount of 1 xe2x88x92100 mol %, preferably 10mol %.
The reaction is carried out in solvents such as ethers, preferably in THF; at a reaction temperature from xe2x88x9280xc2x0 to +80xc2x0, especially preferred at xe2x88x9220xc2x0.
In step 4.2, the compound of formula (7) is treated in a basic medium with HalP(O)(OR)2, wherein Hal is a halogen such as Cl or Br and R is a lower-alkyl group or an aryl group, first to form an enolphosphate and subsequently to eliminate phosphate according to the method described in E. Negishi, A. O. King, J. M. Tour, Org. Synth. 64, 44, 1986, to yield the anion of 8-tert-butoxy-4,4-dimethyl-oct-1-yne of formula: 
The reaction is carried out in the presence of a strong, non-nudeophilic base such as LiN(SiMe3)2, preferably lithium diisopropylamide (LDA).
The reaction is further carried out in solvents such as toluene or ethers, preferably THF and at a reaction temperature of xe2x88x92100xc2x0 to xe2x88x9220xc2x0 for the enolphosphate formation, preferably at xe2x88x9280xc2x0; and for the phosphate elimination at a reaction temperature of xe2x88x9220 to +60xc2x0, preferably at 20xc2x0.
In step 4.3, a ketone of formula Oxe2x95x90CR1R2 is coupled with the anion of 8-tert-butoxy-4,4-dimethyl-oct-1-yne to obtain alkyne-ol derivatives of formula (8).
Preferred ketones of formula Oxe2x95x90CR1R2 are those wherein R1 and R2 are independently of each other lower alkyl or lower perfluoroalkyl, especially preferred ketones are those wherein R1 and R2 are CF3.
The reaction is carried out in the presence of a base and in a solvent as described in step 4.2, at a reaction temperature from xe2x88x92100xc2x0 to xe2x88x9220xc2x0, preferably at a temperature of xe2x88x9280xc2x0.
In step 4.4, the alkyne-ol derivative of formula (8) is treated with hydrogen in the presence of a hydrogenation catalyst to obtain alkene compounds of formula (9), preferably a cis-configurated alkene compound of formula (9).
Such a hydrogenation catalyst is for example Palladium on carbon or a Lindlar catalyst, which is palladium on various supports, such as carbon, BaSO4 or CaCO3, poisoned with lead.
The hydrogenation is carried out in hydrocarbons such as toluene, or in esters such as ethyl acetate, or in ethers, preferably TBME, at a reaction temperature of xe2x88x9220xc2x0 to +60xc2x0, a pressure of 105 to 107 Pa, preferably at a temperature of 22xc2x0 and a pressure of 105 Pa.
Step 4.4 is omitted for the preparation of compounds of formula I wherein A is a triple bond.
Starting from compound of formula (9), the synthesis of compounds of formula IIIa is carried out according to the reaction depicted in scheme 5. 
wherein the symbols are as defined above and R5 is lower alkyl.
In step 5.1, alkene compounds of formula (9) are treated with an acid, to deprotect the protected hydroxy function and to form the hydroxy derivative of the compound of formula
The acids used in this reaction are sulfonic acids such as toluene sulfonic acid, or strong mineral acids such as hydrochloric acid or phosphoric acid, an especially preferred acid is sulfuric acid. The solvents used in this reaction are as described for step 3.4.
In step 5.2, the deprotected hydroxy group of the derivative of formula (9) is then oxidized according to step 2.3, to obtain the corresponding aldehyde-derivative of compound of formula (9).
In step 5.3, the hydroxy group of the aldehyde is protected by reacting the compound with HalY, wherein Hal is a halogen such as Br or I, preferably Cl and Y is as defined above, preferably SiMe3, especially preferred SiEt3, to obtain the compound of formula Va.
The reaction in step 5.3 is carried out in the presence of a base and dimethylamino pyridine as an additive. Bases used in this reaction are amines such as NEt3.
The reaction is carried out in solvents such as hydrocarbons, e.g. toluene; esters e.g. ethyl acetate, or ethers, preferably THF; at a reaction temperature from xe2x88x9220xc2x0 to 60xc2x0, preferably at a temperature of 20xc2x0.
Compounds of formula Va are also used for the preparation of retiferol derivatives according to method B (see scheme 6 below).
In step 5.4, the compound of formula Va is reacted with commercial available Me3SiCH2CO2R5, Ph3Pxe2x95x90CHxe2x80x94CO2R5 or preferably (EtO)2P(O)CH2CO2R5 in the presence of a base to obtain the unsaturated ester derivative of formula (10), wherein R5 is lower alkyl, preferably methyl or especially preferred ethyl.
Bases for the above reaction are strong, non-nucleophilic bases such as LDA or LiN(SiMe3)2, a preferred base is tert-butylOK.
The reaction is carried out in solvents such as ethers, preferably THF or hydrocarbons, an especially preferred solvent is toluene; at a reaction temperature from xe2x88x92100xc2x0 to xe2x88x9220xc2x0, preferably at xe2x88x9280xc2x0.
Compounds of formula (10) are new and therefore form part of the invention. Preferred are compounds of formula (10) wherein Y is a SiMe3 group, an especially preferred compound of formula (10) is wherein Y is a SiEt3, R1 and R2 are CF3 groups and R5 is an ethyl group.
In step 5.5a, the ester group of the compound of formula (10) is reduced in the presence of a reducing reagent to form the hydroxy derivative of the compound of formula (10).
The reaction is carried out with commercially available reducing agents, such as Red-Al(copyright) or LiAIH4, the preferred reducing agent is diisobutylaluminium hydride (DIBAH). In this reaction solvents are used, such as hydrocarbons, preferably toluene; ethers preferably, THF and the reaction temperature ranges from xe2x88x92100xc2x0 to +60xc2x0, a preferred temperature is xe2x88x9280xc2x0.
In step 5.5b, the hydroxy derivative of the compound of formula (10), obtained through step 5.5a, is coupled with an activating agent in the presence of a base and a reagent according to the Mitsunobu method to obtain the sulfanyl-compound of formula (11).
The reaction is carried with commercially available activating reagents, such as 5-mercapto-1-phenyl-tetrazole, a preferred activating reagent is 2-mercapto-benzothiazole.
The reaction is carried out under the following conditions: in the presence of bases such as PAr3, preferably PPh3; with reagents such as C1-4-alkyl azodicarboxylates, preferably iso-propyl azodicarboxylates (for safety reasons); in solvents such as ethers, preferably THF; esters such as ethyl acetate; hydrocarbons such as toluene or halogenated hydrocarbons; at a reaction temperature from xe2x88x9260xc2x0 to +60xc2x0, preferably at a temperature of 0xc2x0.
Compounds of formula (11) are new and therefore form part of the invention. Preferred are compounds of formula (11) wherein Y is a SiMe3 group, especially preferred are compounds of formula (11) wherein Y is SiEt3 and R1 and R2 are CF3 groups.
In step 5.6, the sulfanyl-compounds of formula (11) are oxidized in the presence of an oxidant to obtain sulfonyl-compounds of formula IIIa.
Oxidation methods are oxidations in the presence of 3-chloroperbenzoic acid (MCPBA), Oxones(copyright) (2KHSO5.KHSO4.K2SO4) or H2O with ammonium heptamolybdate-tetrahydrate as a catalyst.
The reaction is carried out with solvents such as halogenated hydrocarbons, preferably CH2Cl2; or alcohols such as ethanol; at a reaction temperature from xe2x88x9220xc2x0 to +70xc2x0, the preferred reaction temperature is in the range of 0xc2x0 to 22xc2x0.
Compounds of formula IIIa are new and therefore form part of the invention. Preferred are compound of formula IIIa wherein Y is a SiMe3 group, especially preferred are compounds of formula IIIa wherein Y is SiEt3 and R1 and R2 are CF3 groups.
Retiferol derivatives of formula I can also be prepared by the coupling of phosphinoxides of formula IV with aldehydes of formula V according to method B (scheme A). It has been found that with processes described below the yield for the preparation of retiferol derivatives of formula I is significantly increased.
A further aspect of the invention is thus the coupling of phophine oxides of formula IV, wherein R4 is a mono alkyl dimethyl-silyl group [Si(C1-4-alkyl)Me2] (compounds of formula IVa) with aldehydes of formula V, wherein A is a double bond and Y a SiEt3 group (compounds of formula Va) to obtain retiferol derivatives of formula Ia according to scheme 6, 
where the symbols are as defined above.
In step 6.1, phosphine oxides of formula IVa are reacted with aldehydes of formula Va, according to a Wittig-Horner reaction, to obtain fully hydroxy group protected retiferol derivatives of compounds of formula Ia.
The reaction is carried out in the presence of a strong base, such as LiN(SiMe3)2 or LDA, a preferably base is n-BuLi; and solvents are used such as hydrocarbons e.g. toluene or ethers preferably tetrahydrofurane (THF); at a reaction temperature from xe2x88x92100xc2x0 to +60xc2x0, the preferred temperature for this reaction is in the range from xe2x88x9280xc2x0 to 20xc2x0.
In step 6.2, the hydroxy protecting groups are cleaved, which can be effected by tetrabutylammonium fluoride (TBAF) in an inert solvent such as tetrahydrofuran to obtain compounds of formula Ia, as described in WO 99/43646.
Especially preferred are processes for the preparation of compounds of formula I wherein A represents a cis configurated double bond xe2x80x94CHxe2x95x90CHxe2x80x94.
Further preferred are processes for the preparation of compounds of formula I wherein A is xe2x80x94Cxe2x95x90Cxe2x80x94, for example (1R,3R)-5-[(2E,9Z)-12,12,12-trifluoro-11-hydroxy-7,7-dimethyl-11-trifluoromethyl-dodeca-2,9-dienylidene)-cyclohexane-1,3-diol.
In the following, the inventive processes for the preparation of intermediates IV is described. The synthesis of compound of formula Va is already described, as part of the reaction in schemes 4 and 5 (steps 4.1-4.4 and 5.1-5.3)
The compounds of formula IV may be prepared according to EP 0516410. However, it has been found that these compounds are prepared more effectively in a lower number of reaction steps and in a higher yield by the processes depicted in scheme 7 and 8, namely by a new process for the stereospecific synthesis of compounds of formula IVa.
A further aspect of the invention is thus the stereospecific synthesis of phosphinoxides of formula IVa, according to scheme 7. 
wherein R3 signifies lower alkyl or mono chlorinated lower alkyl and R4 is a mono alkyl dimethyl-silyl group [Si(C1-4-alkyl)Me2].
In step 7.1, bis acylated ketones of formula IIa, which are prepared as described in steps 2.1-2.3, are reacted with commercial available Me3SiCH2COOEt in the presence of a base according to EP 0516410 B1, to obtain the corresponding protected unsaturated ester derivative of the compound of formula (12).
In step 7.2, the protected hydroxy groups of the unsaturated ester derivative of the compound of formula (12) are deprotected in the presence of a base, to obtain a compound of formula (12). The reaction is carried out as described in step 1.2.
Further, the above reaction is preferably carried out in methanol.
In step 7.3, the hydroxy groups of compound of formula (12) are protected by reaction with a protecting reagent in the presence of a base, to obtain protected derivative of compound of formula (13).
The above reaction is carried out with tert-butyldimethylsilyl triflate (TBSOTf) as protecting reagent or preferably with tert-butyldimethylsilyl chloride (TBSCl). Both protecting reagents yield to a hydroxy protected compound of formula (13), wherein R4 is a tert-butyldimethyl-silyl group (TBS).
Further the reaction is carried out under the following conditions: in the presence of commercially available bases such as pyridine, dimethylpyridine (lutidine), NEt3 or (iso-propyl)2NEt or preferably with imidazole; in solvents such as CH3CN, CH2Cl2, THF or preferably N,N-dimethylformamide (DMF); at a reaction temperature from xe2x88x9260 to +50xc2x0 or at a preferred temperature of 20xc2x0.
In step 7.4, the ester group of the compound of formula (13) is reduced in the presence of a reducing reagent such as Red-Al(copyright), to a hydroxy compound of formula (14), as described in step 5.5a or in EP 0516410.
The reaction is carried out at a reaction temperature of xe2x88x9215xc2x0.
In step 7.5, the compound of formula (14) is treated with benzosulfochloride or preferably with tosyl chloride, in the presence of a base, to obtain the corresponding benzosulfo or tosylate derivative of the compound of formula (14).
The reaction is carried out under the following reaction conditions: with bases such as LDA, preferably n-BuLi; in solvents such as ethers, preferably THF, at a reaction temperature from xe2x88x92100xc2x0 to 0xc2x0, preferably at a reaction temperature of xe2x88x9278xc2x0.
In steps 7.6 and 7.7, the tosylated or benzosulfonated derivative of the compound of formula (14) is reacted first with HPPh2, in the presence of n-BuLi, and subsequently with H2O to obtain the corresponding phophine oxide of formula IVa. The reactions of step 7.6 and 7.7 are carried out according to EP 0516410.
A further embodiment of the invention is a second stereospecific process for the preparation of compounds of formula IVa, which is performed according to scheme 8, starting with compound of formula IIb, prepared according to scheme 3, 
wherein the symbols are as defined above and R4 is a mono alkyl dimethyl-silyl group [Si(C1-4-alkyl)Me2], preferably a mono (C1-C4) alkyl dimethyl-silyl group [Si(C1-4-alkyl)Me2], especially preferred is a tert-butyldimethyl-silyl group (TBS).
In step 8.1, compounds of formula IIb are reacted with commercial available Me3SiCH2COOEt in the presence of a base according to EP 0516410 or as described in step 7.1, to obtain the corresponding unsaturated ester derivative of compound of formula IIb.
In steps 8.2 and 8.3, the tert-butylOCO group of bis-hydroxy protected unsaturated ester derivative of compound of formula IIb is first cleaved to form a hydoxy group, obtaining the corresponding mono hydroxy derivative of compound of formula IIb, which is reacted with a protecting reagent as above defined, to obtain the protected ester compound of formula (13).
The reaction of step 8.2 is carried out, as described in step 3.4 and the reaction of step 8.3 is carried out, as described in step 7.3.
In summary (scheme B), the invention is thus concerned with new processes for the preparation of retiferol derivatives of formula I, namely by
method A (steps 1.1-1.2) which comprises the coupling of ketones of formula II with compounds of formula III or by
method B (steps 6.1-6.2) which comprises the coupling of phosphinoxides of formula IV with aldehydes of formula V.
The compounds of formula II are prepared according
step 2.1-2.3 via an enzymatic hydrolyzation reaction or
step 3.1-3.5 via an enzymatic acylation reaction.
The compounds of formula III are prepared according step 5.1-5.6 via compounds of formula V. 
In these examples, the abbreviations used have the following significances.